HER2-Positive Metastatic Colorectal Cancer.

Opinion statement: Targeted treatment strategies are available for human epidermal growth factor receptor 2 (HER2)-positive (amplified and/or overexpressed) metastatic colorectal cancer (mCRC), and HER2 testing is indicated in patients with mCRC. At present, standard of care first-line treatment for those with HER2-positive mCRC remains chemotherapy in combination with epidermal growth factor receptor (EGFR) inhibitors or bevacizumab, depending on RAS/BRAF mutational status and tumor sidedness. HER2-targeted agents should be considered for those with RAS/BRAF wild-type disease in subsequent-line treatment and in first-line treatment for patients not appropriate for intensive therapy. While the choice of anti-HER2 therapy is empiric given lack of head-to-head comparisons, the combination of trastuzumab plus tucatinib has received FDA accelerated approval for use in this setting and is generally the authors' preference. Trastuzumab plus lapatinib, trastuzumab plus pertuzumab, and trastuzumab deruxtecan (T-DXd) also have evidence of efficacy in this setting. As T-DXd has demonstrated activity following treatment with other HER2-targeted regimens and carries an increased risk of high-grade toxicities, the authors favor reserving it for use after progression on prior anti-HER2 therapy. HER2-targeted therapies that inhibit signal transduction appear to have limited activity in those with RAS mutations, including trastuzumab-containing regimens. However, the antibody drug conjugate T-DXd has some data showing efficacy in this setting, and the authors would consider T-DXd in subsequent-line therapy for HER2-positive, RAS-mutated mCRC. Several areas of uncertainty remain regarding how to best utilize HER2-targeted therapies in mCRC. These include the optimal sequence of anti-HER2 therapies with chemotherapy and anti-EGFR therapies, the optimal combination partners for anti-HER2 therapies, and the incorporation of predictive biomarkers to guide use of anti-HER2 therapies. Results of ongoing studies may thus alter the treatment paradigm above in the coming years.